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Pharmacogenetic association studies and the impact of population substructure in the women's interagency HIV study

PHARMACOGENETIC ASSOCIATION STUDIES AND
THE IMPACT OF POPULATION SUBSTRUCTURE
IN THE WOMEN’S INTERAGENCY HIV STUDY
by
Melissa Ann Frasco
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(EPIDEMIOLOGY)
August 2012
Copyright 2012 Melissa Ann Frasco

Population stratification can result in spurious associations in genetic studies when the outcome and genotype are associated with genetic ancestry. The objective of this dissertation was to characterize population substructure in the Women’s Interagency HIV Study (WIHS), a cohort of HIV-infected and uninfected participants in the United States (U.S), and assess the impact of population substructure on genetic association studies. First, population substructure was characterized using genotype data on 168 ancestry informative markers (AIMs) by performing a Bayesian clustering algorithm to infer genetic membership in three and four assumed source populations. Principal components (PC) analysis was conducted to generate continuous genetic ancestry covariates to use as covariates in genetic association statistical models. Population substructure was identified within self-identified ethnic groups and across geographical regions in the U.S., exemplifying the importance of estimating individual genetic ancestry to control for residual ethnic confounding in genetic association studies. Cautious interpretation of ancestry admixture estimates should be exercised, as the labeling of source populations is sensitive to the panel of markers and referent populations used in analyses. ❧ The effect of variation in CYP2B6 on virologic response to its substrates, the nonnucleoside reverse transcriptase inhibitors (NNRTIs), was explored with consideration for self-reported race/ethnicity and underlying genetic structure. Logistic regression was used to test the joint effect of two single nucleotide polymorphisms (SNP) rs3745274 and rs28399499, which comprise the CYP2B6 metabolizer phenotype indicating slow, intermediate and extensive metabolizers. Substantial evidence of confounding was present with the metabolizer phenotype when comparing the crude, self-reported ethnicity-adjusted and genetic ancestry PCs-adjusted estimates. Women classified as intermediate and slow metabolizers were 2.90 (95% CI 0.79-12.28) and 13.44 (95% CI 1.66-infinity) times as likely to achieve virologic suppression compared to extensive metabolizers after adjustment for PCs (p trend =0.005). The CYP2B6 metabolizer phenotype was significantly associated with response to NNRTIs, a relation that would have been masked by simply adjusting for self-reported race/ethnicity (p for trend=0.04 after adjustment for self-reported race/ethnicity). ❧ Type 2 diabetes (T2D) in the setting of HIV infection is a concern given the prevalence of HIV-related conditions that contribute to the etiology T2D. The incidence of T2D varies substantially between racial/ethnic groups and thus control for genetic substructure is imperative in genetic association studies of T2D risk. Eighteen previously confirmed T2D-associated SNPs were tested using Cox proportional hazard models with adjustment for genetic ancestry principal components using age for the time-scale. Exposure to nucleoside reverse transcriptase inhibitors (NRTI), a T2D risk factor, was explored as an effect modifier. Overall, the T2D risk conferred by these SNPs was similar in White/Hispanic HIV-infected women compared to HIV-uninfected European individuals, as evaluated by the effect measures and p values for heterogeneity. The magnitude of each SNP effect was smaller in African-American women (HRs~1.1). Significant interactions were revealed between these T2D-associated SNPs and NRTI exposure (p<0.03) in White/Hispanic women. ❧ This dissertation confirmed prior report of the role of CYP2B6 SNPs in NNRTI metabolism and efficacy. Additionally, the role of T2D-associated SNPs in the context of HIV was validated and the synergistic effect of T2D-associated SNPs and NRTIs on the risk of T2D was suggested. Substantial evidence of residual confounding was revealed in both studies, which highlights the importance of controlling for population substructure using genetic ancestry estimates in genetic association studies.

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PHARMACOGENETIC ASSOCIATION STUDIES AND
THE IMPACT OF POPULATION SUBSTRUCTURE
IN THE WOMEN’S INTERAGENCY HIV STUDY
by
Melissa Ann Frasco
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(EPIDEMIOLOGY)
August 2012
Copyright 2012 Melissa Ann Frasco